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Targeting transgene expression specifically to antigen-presenting cells (APCs) has been put forward as a promising strategy to direct the immune system towards immunity. We developed the nanobody-display technology to restrict the tropism of lentiviral vectors (LVs) to APCs. However, we observed that immunization with APC-targeted LVs (DC2.1-LVs) did not evoke strong antigen-specific T-cell immunity when compared to immunization with broad tropism LVs (VSV.G-LVs). In this study, we report that VSV.G-LVs are more immunogenic than DC2.1-LVs because they transduce stromal cells, which has a role in activating antigen-specific T cells. Moreover, VSV.G-LVs trigger a pro-inflammatory innate immune response through transduction of APCs and stromal cells, while DC2.1-LVs trigger a type I interferon response with anti-viral capacity. These findings question the rationale of targeting LVs to APCs and argue for the development of VSV.G-LVs with an improved safety profile.